EP0418806B1 - Pharmaceutical compositions havin activity on the cutaneous microcirculation - Google Patents
Pharmaceutical compositions havin activity on the cutaneous microcirculation Download PDFInfo
- Publication number
- EP0418806B1 EP0418806B1 EP90117916A EP90117916A EP0418806B1 EP 0418806 B1 EP0418806 B1 EP 0418806B1 EP 90117916 A EP90117916 A EP 90117916A EP 90117916 A EP90117916 A EP 90117916A EP 0418806 B1 EP0418806 B1 EP 0418806B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- visnadine
- ammi
- activity
- pharmaceutical
- cosmetic compositions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/008—Preparations for oily hair
Definitions
- the present invention concerns pharmaceutical and cosmetic compositions comprising extracts of Ammi visnaga and Ammi majus or the vasoactive agents contained therein, particularly visnadine, kelline and other coumarins and flavoncoumarols.
- the compositions of the invention are useful for the topical, epicutaneous treatment of pathological or paraphysiological conditions of the skin and of the adnexes thereof, characterized by functional or organic deficiencies of the local microcirculation associated with ischemia, stasis and trophic disturbances secondary to impaired microvascular-tissue relationships.
- the compound is not convenient to use, it asks for high daily doses, it must be administered for prolonged periods and produces favourable responses in an unsatisfactorily low proportion of patients.
- the administration of these high dosages for long period is associated with remarkable side-effects, especially gastric disturbances, insomnia and paresthesiae which may even require discontinuation of the therapy.
- the available knowledges refer only to the treatment of disorders affecting large arteries and of pathological conditions of peripheral vascular diseases secondary to occlusion of large arterial vessels, without any mention of a possible effect of the compound on the microcirculation and on the smallest arterio-arteriolar vessels at precapillary level, with particular reference to the cutaneous circulation.
- the invention refers therefore to pharmaceutical and cosmetic compositions comprising extracts of Ammi visnaga and Ammi majus containing visnadine and/or visnadine-like coumarins and flavoncoumarols, or visnadine itself in purified form incorporated in a liposomal vehicle for the therapeutic treatment by the topical epicutaneous route of peripheral vascular acrosyndromes, particularly of Raynaud disease and of local perfusion deficiencies of the upper and lower limbs, and for the cosmetic treatment of defects due to insufficient blood perfusion of the skin and of the subcutaneous adipous tissue, particularly for the treatment of precocious senile involution of the face and neck skin, cellulitis, cutaneous stretch marks, alopecias and similar conditions.
- the percutaneous administration is not only surprisingly more active and effective but it is also practically devoid of side-effects such as those described for the oral administration of high doses.
- the active and effective doses by topical epicutaneous route are by far lower, up to 50 times, than that used for the oral route and the time necessary for the onset of the biological effect, which may be measured by means of instrumental methods, is of some hours whereas the oral route asks for days or months.
- compositions of the invention may be prepared using known methods and excipients, such as those disclosed in "Remington's Pharmaceutical Sciences Handbook” Mack Pub. Co., NY, USA.
- suitable formulations include creams, ointments, gel, lotions containing from 1 to 5% of visnadine or the equivalent of extracts or of visnadine-like compounds (visnaginone, kelline, kellinone, coumarins, dihydropyranocoumarins or dihydrofuranocoumarins derived from plants of the Ammi genus).
- formulations may be applied on the skin so as to cover the area to be treated once or more times a day.
- Liposomial carriers obtainable from lecithins, unsaturated or saturated phosphatidylcholine or other conventional phospholipids are particularly preferred.
- the Ammi extracts may be obtained according to known methods, such as those disclosed in the following Examples wherein specific reference is made to visnadine. It is however apparent that all the above cited extracts containing visnadine or the above cited visnadine-like compounds contained in plants of the Ammi genus may be used in substitution of or in combination with visnadine, in any quantitative ratio.
- 100 Kg of finely ground blossoming tops of the plant are placed in a 400 l extractor suited for the use of gases in hypercritic conditions; the plant material is extracted with carbon dioxide for 1 h at 35°C and under a pressure of 100 bar to remove the undesired fatty substances; after elimination of the extract from the condenser, the extraction with carbon dioxide is continued at 45°C and 180 bar for 3 h or until complete extraction of visnadine from the plant material.
- the obtained extract (3.4 kg) may be directly used or it may be subjected to purification by partition between immiscible solvents according to the methods of Example 3.
- composition 100 g of composition contain:
- Gel containing as active principle a mixture of visnadine and kelline 100 g of gel contain:
- the sphygmic activity of small arteries and arterioles of the subpapillary plexus and the cutaneous temperature of the fingertip were determined quantitatively in 30 healthy subjects (divided in two groups A and B) by using computerized infra-red photo-pulse plethysmography (i.r.Ph.P.P.) and direct cutaneous thermometry respectively. The same measurements were repeated at 15, 30 , 45 and 60 minutes after the percutaneous application of a visnadine formulation (prepared according to Example I) in group A and placebo in group B. The application was always followed by a light massage until complete penetration of the product had been achieved.
- a visnadine formulation prepared according to Example I
- Example I As indicated by the data shown in Table 1, the preparation described in Example I induces a statistically significant increase in the arterio- arteriolar sphygmic activity as compared to baseline conditions. This, in turn, determines an increase in volume and velocity of the microcirculatory flow directed to the capillary networks located downstream, with consequent elevation of the cutaneous temperature without reddening and without active hyperemia. The placebo was found to be totally inactive.
- arterio-arteriolar sphygmic activity of the fingertip and the cutaneous temperature under baseline conditions and after immersion of the right hand in an ice-water bath for 4 minutes were determined in healthy subjects divided into two groups (group A and group B) as in investigation A.
- group A and group B The skin of the fingers and of the palmar and dorsal surface of the hand was treated with a visnadine preparation or with placebo as described in Example I and investigation A.
- Continuous computerized recordings of arterio-arteriolar sphygmicity and of cutaneous temperature were made as in investigation A until all values had returned to baseline conditions, and the required time (in minutes) was calculated.
- Investigation C was performed in subjects with venous stasis and/or chronic venous insufficiency of the lower limbs and functional-anatomic alterations of the cutaneous arterio-arteriolar afferrents.
- the subjects were divided into two groups (group A and group B) as in investigation A.
- the filling time of the superficial venous plexus of the dorsum of the foot was recorded in these subjects by means of light reflectance rheography before and after 15 timed rhythmical flexion-extension movements of the foot.
- the profile of the resulting recording represents a mirror image of the venous pressure in the system.
- the preparation was applied twice daily over the entire surface of the lower limb, including the thigh.
- the experimental protocol was carried out according to a placebo-controlled, double-blind design.
- the arterio-arteriolar sphygmic activity of the subpapillary plexus of the supra-lateral region of the thigh was recorded in parallel by means of computerized infra-red plethysmography.
- Investigation D was performed in a group of male subjects with alopecia aerata.
- the local microcirculatory conditions in the scalp area affected by the disease were evaluated by means of high-resolution contact thermometry and infra-red photo-plethysmography before and 60 minutes after the application of a hair lotion containing visnadine prepared according to Example 4.
- the instrument-based data indicate that the sphygmic waves of the arteries in the fingertip of treated fingers exhibit after treatment a statistically significant increase in amplitude as compared to placebo.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Alternative & Traditional Medicine (AREA)
- Birds (AREA)
- Dermatology (AREA)
- Dispersion Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
- The present invention concerns pharmaceutical and cosmetic compositions comprising extracts of Ammi visnaga and Ammi majus or the vasoactive agents contained therein, particularly visnadine, kelline and other coumarins and flavoncoumarols. The compositions of the invention are useful for the topical, epicutaneous treatment of pathological or paraphysiological conditions of the skin and of the adnexes thereof, characterized by functional or organic deficiencies of the local microcirculation associated with ischemia, stasis and trophic disturbances secondary to impaired microvascular-tissue relationships.
- The therapeutic use of extracts of Ammi visnaga and Ammi majus or of active constituents thereof is already known, particularly in the cardiological field for the treatment of ischemic coronaropathies, namely of anginous attacks and of chronic-degenerative myocardial diseases. More recently, it has been reported that some dihydropyranocoumarins and dihydrofuranocoumarins are endowed with platelet anti-aggregant activity similar to that of dipyridamol; this could lead to their therapeutic uses as anti-thrombotic agents and cyclic AMP-phosphodiesterase inhibitors. Some derivatives of visnaginone and of kellinone were reported to be endowed with antibacterial and anti-helmintic activity. High oral doses of visnadine have been used by BENSIMON (G.M. de France, Tome 77, No. 29, 1970, 6269-6275) and by GOURNAY (G.M. de France, Tome 78, No. 3, 1971, 390-391) in the treatment of peripheral arteriopathies affecting large arterial vessels.
- The results of said studies show that: the compound is not convenient to use, it asks for high daily doses, it must be administered for prolonged periods and produces favourable responses in an unsatisfactorily low proportion of patients. Moreover, the administration of these high dosages for long period is associated with remarkable side-effects, especially gastric disturbances, insomnia and paresthesiae which may even require discontinuation of the therapy.
- The available knowledges refer only to the treatment of disorders affecting large arteries and of pathological conditions of peripheral vascular diseases secondary to occlusion of large arterial vessels, without any mention of a possible effect of the compound on the microcirculation and on the smallest arterio-arteriolar vessels at precapillary level, with particular reference to the cutaneous circulation.
- It has now been found according to the present invention that the extracts of Ammi visnaga and Ammi majus containing visnadine and/or coumarins as well as visnadine-like flavoncoumarols and visnadine itself in purified form, have the following properties:
- a) they are not "vasodilators" and therefore they do not inhibit the tonus and the sphygmic activity of the muscular media in medium-sized or large arteries. By contrast, they exert a marked stimulatory effect on microvascular motility and on the sphygmic activity of the smooth muscle constituents of the media of small arteries and precapillary arterioles. The supposed "vasodilator effect" is only a consequence of substantial modifications in the microcirculatory haemodynamics;
- b) their biological effect is therefore mainly at microcirculatory level. These agents act infact on small arteries and precapillary arterioles and determine as an immediate haemodynamic consequence increase of the volume and of the blood flow-rate in capillary network: the tissue oxygenation increases and the trophic exchanges are enhanced;
- c) they are highly effective in antagonizing the vasal spasm induced by cold, particularly in the circulation of the fingertip.
- The invention refers therefore to pharmaceutical and cosmetic compositions comprising extracts of Ammi visnaga and Ammi majus containing visnadine and/or visnadine-like coumarins and flavoncoumarols, or visnadine itself in purified form incorporated in a liposomal vehicle for the therapeutic treatment by the topical epicutaneous route of peripheral vascular acrosyndromes, particularly of Raynaud disease and of local perfusion deficiencies of the upper and lower limbs, and for the cosmetic treatment of defects due to insufficient blood perfusion of the skin and of the subcutaneous adipous tissue, particularly for the treatment of precocious senile involution of the face and neck skin, cellulitis, cutaneous stretch marks, alopecias and similar conditions.
- The percutaneous administration is not only surprisingly more active and effective but it is also practically devoid of side-effects such as those described for the oral administration of high doses.
- The active and effective doses by topical epicutaneous route are by far lower, up to 50 times, than that used for the oral route and the time necessary for the onset of the biological effect, which may be measured by means of instrumental methods, is of some hours whereas the oral route asks for days or months.
- The pharmaceutical or cosmetic compositions of the invention may be prepared using known methods and excipients, such as those disclosed in "Remington's Pharmaceutical Sciences Handbook" Mack Pub. Co., NY, USA.
- Examples of suitable formulations include creams, ointments, gel, lotions containing from 1 to 5% of visnadine or the equivalent of extracts or of visnadine-like compounds (visnaginone, kelline, kellinone, coumarins, dihydropyranocoumarins or dihydrofuranocoumarins derived from plants of the Ammi genus).
- These formulations may be applied on the skin so as to cover the area to be treated once or more times a day.
- Liposomial carriers obtainable from lecithins, unsaturated or saturated phosphatidylcholine or other conventional phospholipids are particularly preferred.
- The Ammi extracts may be obtained according to known methods, such as those disclosed in the following Examples wherein specific reference is made to visnadine. It is however apparent that all the above cited extracts containing visnadine or the above cited visnadine-like compounds contained in plants of the Ammi genus may be used in substitution of or in combination with visnadine, in any quantitative ratio.
- 100 g of visnadine are dissolved together with 400 g of pure soy-bean phosphatidylcholine in 1 l of methylene chloride; the solvent is evaporated under vacuum and the syrupy residue is dispersed in 5 l of water in an high speed turboemulsifier under strong stirring for 5 h; 200 g of mannitol are then added and the mixture is distributed in 10 ml vials and lyophilized. This lyophilized material, suspended in 5 ml of water, is directly applied on the cutis to be treated.
- 100 Kg of finely ground blossoming tops of the plant are placed in a 400 l extractor suited for the use of gases in hypercritic conditions; the plant material is extracted with carbon dioxide for 1 h at 35°C and under a pressure of 100 bar to remove the undesired fatty substances; after elimination of the extract from the condenser, the extraction with carbon dioxide is continued at 45°C and 180 bar for 3 h or until complete extraction of visnadine from the plant material. The obtained extract (3.4 kg) may be directly used or it may be subjected to purification by partition between immiscible solvents according to the methods of Example 3.
- 2.5 Kg of lipophilic extract prepared according to Example 2 are dissolved in 25 l of 95% aqueous methanol and thoroughly extracted with 20 l of n-hexane until complete extraction of the extractable undesired material; the pooled hexane extracts are counter-washed with 5 l of 95% methanol which are added to the previous methanol phase. The methanol solution is concentrated under vacuum up 10 l and the concentrate is diluted with an equal volume of water; the obtained suspension is counter-extracted with n-hexane until complete extraction of visnadine. After addition of a 3% proportion of ethanol, the hexane solution is concentrated resulting in crystallization of the desired product which exhibits spectroscopic and physico-chemical characteristics equivalent to those described in literature.
- Lotion for the treatment of hair scalp.
-
- Gel containing as active principle a mixture of visnadine and kelline
100 g of gel contain: - Visnadine
- 1 g
- Kelline
- 0,5 g
- SoftigenR 727
- 25 g
- VolpoR 20
- 7 g
- CarbopolR 934
- 1,5 g
- Triethanolamine
- 1 g
- Imidazolidinylurea
- 0,3 g
- Purified water
- q.s. to 100 g
- The sphygmic activity of small arteries and arterioles of the subpapillary plexus and the cutaneous temperature of the fingertip were determined quantitatively in 30 healthy subjects (divided in two groups A and B) by using computerized infra-red photo-pulse plethysmography (i.r.Ph.P.P.) and direct cutaneous thermometry respectively. The same measurements were repeated at 15, 30 , 45 and 60 minutes after the percutaneous application of a visnadine formulation (prepared according to Example I) in group A and placebo in group B. The application was always followed by a light massage until complete penetration of the product had been achieved.
- As indicated by the data shown in Table 1, the preparation described in Example I induces a statistically significant increase in the arterio- arteriolar sphygmic activity as compared to baseline conditions. This, in turn, determines an increase in volume and velocity of the microcirculatory flow directed to the capillary networks located downstream, with consequent elevation of the cutaneous temperature without reddening and without active hyperemia. The placebo was found to be totally inactive.
- These data indicate that, surprisingly, visnadine:
- Acts selectively on the small arteries and arterioles of the cutaneous microcirculation;
- Increases the volume of blood in the capillaries and opens to blood flow previously closed vessels in capillary networks. This results in increased cutaneous temperature and enhanced trophic exchanges even in normal, healthy subjects;
- Is active by direct topical epicutaneous application to the desired site of action at dosages much lower than those used by the oral route.
- In addition, the effects of topical epicutaneously applied visnadine are surprisingly more rapid and can be demonstrated readily by instrument-based measurements, as opposed to the situation observed after oral administration of doses at least 50-fold greater.
- The arterio-arteriolar sphygmic activity of the fingertip and the cutaneous temperature under baseline conditions and after immersion of the right hand in an ice-water bath for 4 minutes ("cold test") were determined in healthy subjects divided into two groups (group A and group B) as in investigation A. The skin of the fingers and of the palmar and dorsal surface of the hand was treated with a visnadine preparation or with placebo as described in Example I and investigation A. Continuous computerized recordings of arterio-arteriolar sphygmicity and of cutaneous temperature were made as in investigation A until all values had returned to baseline conditions, and the required time (in minutes) was calculated.
- The results of this investigation clearly show that epicutaneous treatment with the preparation described in Example I causes a statistically significant reduction of the time required for flow conditions to return to baseline, while placebo treatment is without effect. These results demonstrate that visnadine:
- After topical epicutaneous application, counteracts rapidly and effectively the vasoconstriction and the associated decrease in arterio-arteriolar sphygmic activity which follow exposure to cold ("cold test") in healthy subjects;
- Potently antagonizes at microcirculatory level the cold-induced ischemia of the tissue;
- May be used for the topical epicutaneous treatment of functional or organic peripheral vascular acrosyndromes due to microangiopathies and/or histangiopathies and characterized by hypoxic episodes affecting the extremities, secondary to abnormal cold-induced vasoconstriction and deficiency of the mechanisms regulating the local microcirculatory flow;
- After topical epicutaneous application with an adequate vehicle, counteracts the physiological cold-induced vasoconstriction at very low doses.
- Investigation C was performed in subjects with venous stasis and/or chronic venous insufficiency of the lower limbs and functional-anatomic alterations of the cutaneous arterio-arteriolar afferrents. The subjects were divided into two groups (group A and group B) as in investigation A. The filling time of the superficial venous plexus of the dorsum of the foot was recorded in these subjects by means of light reflectance rheography before and after 15 timed rhythmical flexion-extension movements of the foot. The profile of the resulting recording represents a mirror image of the venous pressure in the system. These measurements were repeated by using the same procedure after 3 weeks of epicutaneous treatment with a visnadine preparation of the type described in Example I or in Example 5. The preparation was applied twice daily over the entire surface of the lower limb, including the thigh. The experimental protocol was carried out according to a placebo-controlled, double-blind design. The arterio-arteriolar sphygmic activity of the subpapillary plexus of the supra-lateral region of the thigh was recorded in parallel by means of computerized infra-red plethysmography.
- The results of this investigation indicate that the filling time of the superficial cutaneous venous plexus of the pretibial region is clearly prolonged in subjects treated with visnadine as compared to those treated with placebo, which is on the contrary without effect. Moreover, in visnadine-treated subject the sphygmic activity of the small arteries and arterioles of the subpapillary plexus of the supralateral region of the thigh increases by more than 50% compared to baseline conditions, with a clear-cut improvement in local microcirculatory flow. The subjects treated with the active preparation show an appreciable subjective improvement in the feeling of leg heaviness, paresthesiae and frequency of diurnal and nocturnal muscle cramps.
- The instrument-based findings demonstrate that:
- In the presence of capillaro-venular stasis causing a slowing and a pathological alteration of the microvascular-tissue exchanges, low dosages of topical epicutaneously applied visnadine are surprisingly effective in increasing the velocity and volume of the cutaneous microcirculatory flow, thus counteracting the blood stasis;
- Topically applied visnadine is effective in reducing the microcirculatory stasis and the capillaro-venular dilation typically associated with stasis conditions and/or chronic venous insufficiency. Surprisingly, this activity is already observed at very low doses compared with those used by the oral route. The rapid onset of activity and the efficacy of this treatment can be documented by instrument based observations and are statistically significant as compared to placebo.
- Investigation D was performed in a group of male subjects with alopecia aerata. The local microcirculatory conditions in the scalp area affected by the disease were evaluated by means of high-resolution contact thermometry and infra-red photo-plethysmography before and 60 minutes after the application of a hair lotion containing visnadine prepared according to Example 4.
- The instrument-based findings demonstrate that:
- Topical epicutaneous application of visnadine over the areas of alopecia is effective in increasing arterio-arteriolar sphygmic activity and cutaneous temperature. These effects are associated with an increase in volume/minute and velocity of microcirculatory flow, resulting in improved perfusion of the hair follicle;
- Visnadine does not cause reddening secondary to cutaneous vasodilation, unlike, other drugs or compounds which induce scalp hyperemia and reduce at the same time the volume of the local microcirculatory flow;
- The vehicle (especially phospholipidic liposomes) exerts surprisingly an antiseborrhoic action and reduces the lipidic content of greasy hair. This allows a drastic reduction of the weekly frequency of the required hair washings;
- The dose of visnadine which is active on the scalp microcirculation is much lower than those used orally for the vasodilating treatment of arterial diseases and/or coronary heart disease;
- The action of the compound is exerted essentially by the topical route in the presence of an appropriate (preferably liposomal) vehicle.
- Two groups of patients (group A and group B) with primary or secondary Raynaud's phenomenon were treated topically by epicutaneous application with an active preparation (prepared as described in Examples I and V) or with placebo according to a double-blind design.
- At baseline and after 30 days of treatment the patients were evaluated clinically and instrumentally by means of impedance plethysmography performed on the second, third and fourth finger of both hands.
- The data obtained in this investigation indicate that the percutaneous treatment with the active preparation induces an appreciable clinical improvement which was rated as "excellent" in 43% of the cases and "good" in 26% of the cases. The placebo preparation was found to be ineffective.
- The instrument-based data indicate that the sphygmic waves of the arteries in the fingertip of treated fingers exhibit after treatment a statistically significant increase in amplitude as compared to placebo.
- The clinical and instrument-based findings demonstrate that:
- When applied topically over the extremities of limbs affected by pathological ischemic conditions or arterio-arteriolar spasms causing capillary hypovolemia, visnadine induces a statistically significant improvement of clinical symptoms and instrument-based measurements. These effects are surprisingly already seen at dosages which are 30 to 50-fold lower than those used for the oral treatment of "arteritis", e.g. for their action at the level of large and medium sized arteries.
- The vehicle used to facilitate the penetration across the epidermal barrier is preferably liposomal;
- After topical "transepidermal" administration in pathological conditions (functional spasms of the microcirculation), visnadine exerts an hyperactivating action on the microcirculatory flow which is identical to that observed and documented in the "cold test" performed in healthy subjects (investigation B).
Claims (4)
- Pharmaceutical and/or dermatocosmetic and cosmetic compositions containing extracted or semi-synthetic derivatives of Ammi visnaga and Ammi majus, incorporated in a liposomal vehicle.
- Pharmaceutical and/or dermatocosmetic and cosmetic compositions according to claim 1, in which the liposomal vehicle is based on unsaturated phosphatidylcholine from soy-beans or other extractable animal sources, extracted phospholipidic mixtures, saturated phosphatidylcholine.
- Pharmaceutical and/or dermatocosmetic and cosmetic compositions according to claim 1 and containing visnadine, kelline, kellinone, visnaginone and the other flavoncoumarols , coumarins, dihydropyrano- and dihydrofuranocoumarins derived from Ammi visnaga and Ammi majus, as mixtures or in purified form.
- The use of extracted or semi-synthetic derivatives of Ammi visnaga and Ammi majus for the preparation of a medication exerting microvasculo-kinetic effects or stimulatory effects on the sphygmic activity of small arteries and arterioles.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT90117916T ATE99542T1 (en) | 1989-09-21 | 1990-09-18 | PHARMACEUTICAL COMPOSITIONS ACTING ON SKIN MICROCIRCULATION. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT2178689 | 1989-09-21 | ||
IT8921786A IT1233753B (en) | 1989-09-21 | 1989-09-21 | PHARMACEUTICAL COMPOSITIONS WITH ACTIVITY ON SKIN MICROCIRCULATION. |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0418806A1 EP0418806A1 (en) | 1991-03-27 |
EP0418806B1 true EP0418806B1 (en) | 1994-01-05 |
Family
ID=11186827
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP90117916A Expired - Lifetime EP0418806B1 (en) | 1989-09-21 | 1990-09-18 | Pharmaceutical compositions havin activity on the cutaneous microcirculation |
Country Status (10)
Country | Link |
---|---|
US (1) | US5176919A (en) |
EP (1) | EP0418806B1 (en) |
JP (1) | JP2731976B2 (en) |
KR (2) | KR0128057B1 (en) |
AT (1) | ATE99542T1 (en) |
CA (1) | CA2025855C (en) |
DE (1) | DE69005753T2 (en) |
ES (1) | ES2062240T3 (en) |
HK (1) | HK161095A (en) |
IT (1) | IT1233753B (en) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1269634B (en) * | 1994-05-06 | 1997-04-08 | Indena Spa | TOPICAL MEDICATION WITH CICATRIZING ACTIVITY |
IT1270602B (en) * | 1994-07-12 | 1997-05-07 | Indena Spa | ESCULOSIDE BASED FORMULATIONS AND THEIR USE IN THE PHARMACEUTICAL AND COSMETIC FIELD |
IT1278997B1 (en) * | 1994-07-19 | 1997-12-02 | Indena Spa | COMBINATIONS OF VASOACTIVE SUBSTANCES WITH FATTY ACIDS TO FIGHT HAIR LOSS |
US5755680A (en) * | 1994-11-01 | 1998-05-26 | Ghodsian; Kamran | Method for inhibiting the formation of striations due to skin tension |
BR9908870A (en) * | 1998-03-16 | 2000-11-21 | Procter & Gamble | Processes to regularize the appearance of the skin |
DE19928528C2 (en) * | 1999-06-22 | 2002-10-17 | Heinz Kiefer | Medicines (antiarteriosclerotic) for the prevention and relief of symptoms of arterial circulatory disorders based on ginkgobiloba |
JP4498593B2 (en) * | 2000-11-30 | 2010-07-07 | 株式会社マンダム | Hair restorer composition |
FR2849775B1 (en) * | 2003-01-09 | 2005-02-11 | Gattefosse Ets Sa | COSMETIC COMPOSITION BASED ON CIRSIMARINE |
ITMI20031427A1 (en) * | 2003-07-11 | 2005-01-12 | Indena Spa | COMBINATIONS OF VASOACTIVE AGENTS, THEIR USE IN THE PHARMACEUTICAL AND COSMETIC FIELD AND THE FORMULATIONS THAT CONTAIN THEM |
ITMI20031428A1 (en) | 2003-07-11 | 2005-01-12 | Indena Spa | COMBINATIONS OF VASOACTIVE AGENTS AND THEIR USE FOR THE TREATMENT OF SEXUAL DYSFUNCTIONS |
US20070065377A1 (en) * | 2003-10-17 | 2007-03-22 | Mu-Hyun Jin | Composition for promoting synthesis of collagen, and composition for external preparation for skin comprising the same |
KR100561868B1 (en) * | 2004-03-31 | 2006-03-17 | 삼성전자주식회사 | Apparatus for controlling blood flow using magnetic field and methods for the same |
DE602006015309D1 (en) | 2005-03-12 | 2010-08-19 | Unilever Nv | HAIR AND / OR HEAD CARE COMPOSITIONS USING AMINO OXO INDOLYLIDEN COMPOUNDS |
US20080167284A1 (en) * | 2005-03-12 | 2008-07-10 | Ranjit Bhogal | Hair And/Or Scalp Care Compositions Incorporating Visnadin |
KR101300744B1 (en) * | 2011-05-25 | 2013-08-28 | 강원대학교산학협력단 | Photo-responsive vesicles and preparation method thereof |
CN106177100B (en) * | 2016-08-29 | 2020-04-21 | 欧标(广州)化妆品有限公司 | Composition with acne removing effect and application thereof |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB708484A (en) * | 1951-05-21 | 1954-05-05 | Smith Kline & French Internat | Improvements in or relating to method for isolation and purification of active plantprinciples |
US3553236A (en) * | 1968-12-06 | 1971-01-05 | Franco Indian Pharmaceuticals | Psoralene and isopsoralene, process for their isolation and separation |
US4169204A (en) * | 1976-10-20 | 1979-09-25 | Regents Of The University Of California | Psoralens |
US4284569A (en) * | 1979-02-13 | 1981-08-18 | The Upjohn Company | Antiatherosclerotic furochromones |
US4399146A (en) * | 1979-02-13 | 1983-08-16 | The Upjohn Company | Treatment of atherosclerosis with khellin-related furochromones |
US4313883A (en) * | 1980-01-28 | 1982-02-02 | The Upjohn Company | Halofurochromones |
US4313882A (en) * | 1980-01-28 | 1982-02-02 | The Upjohn Company | 7-Methyl-6-methylthio-, methylsulfinyl-, and methylsulfonyl-methyl-furochromones |
US4304722A (en) * | 1980-01-28 | 1981-12-08 | The Upjohn Company | Benzo[1,2-b:5,4-b']difuran-3(2H)-ones |
US4313881A (en) * | 1980-01-28 | 1982-02-02 | The Upjohn Company | 5-Hydroxyfurochromones |
US4454152A (en) * | 1980-05-07 | 1984-06-12 | Hoffmann-La Roche Inc. | Methoxsalen dosage forms |
US4434295A (en) * | 1982-05-17 | 1984-02-28 | The Upjohn Company | Anti-atherosclerotic 6,7-dihydro-7,7-disubstituted-khellin analogs |
US4438274A (en) * | 1982-05-17 | 1984-03-20 | The Upjohn Company | Antiatherosclerotic furochromones |
US4412071A (en) * | 1982-05-17 | 1983-10-25 | The Upjohn Company | Antiatherosclerotic compositions |
US4542228A (en) * | 1982-05-17 | 1985-09-17 | The Upjohn Company | 4-Hydroxy-furochromone intermediates for antiathersclerotic compounds |
US4540798A (en) * | 1982-05-17 | 1985-09-10 | The Upjohn Company | Antiatherosclerotic aminoethenyl furochromones |
JPS61103833A (en) * | 1984-10-25 | 1986-05-22 | Kao Corp | Promoter for skin blood circulation for external use |
US4937078A (en) * | 1988-08-26 | 1990-06-26 | Mezei Associates Limited | Liposomal local anesthetic and analgesic products |
JPH02167216A (en) * | 1988-09-02 | 1990-06-27 | Kao Corp | Bathing agent |
-
1989
- 1989-09-21 IT IT8921786A patent/IT1233753B/en active
-
1990
- 1990-09-18 AT AT90117916T patent/ATE99542T1/en not_active IP Right Cessation
- 1990-09-18 ES ES90117916T patent/ES2062240T3/en not_active Expired - Lifetime
- 1990-09-18 DE DE90117916T patent/DE69005753T2/en not_active Expired - Fee Related
- 1990-09-18 EP EP90117916A patent/EP0418806B1/en not_active Expired - Lifetime
- 1990-09-20 CA CA002025855A patent/CA2025855C/en not_active Expired - Fee Related
- 1990-09-20 JP JP2251682A patent/JP2731976B2/en not_active Expired - Fee Related
- 1990-09-20 KR KR1019900014946A patent/KR0128057B1/en not_active IP Right Cessation
- 1990-09-20 US US07/585,731 patent/US5176919A/en not_active Expired - Lifetime
-
1995
- 1995-10-12 HK HK161095A patent/HK161095A/en not_active IP Right Cessation
-
1997
- 1997-04-09 KR KR1019970013041A patent/KR0132730B1/en not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
" Rote Liste " 1986 * |
Also Published As
Publication number | Publication date |
---|---|
DE69005753D1 (en) | 1994-02-17 |
CA2025855A1 (en) | 1991-03-22 |
ATE99542T1 (en) | 1994-01-15 |
HK161095A (en) | 1995-10-20 |
DE69005753T2 (en) | 1994-04-28 |
US5176919A (en) | 1993-01-05 |
JP2731976B2 (en) | 1998-03-25 |
KR0128057B1 (en) | 1998-04-01 |
KR0132730B1 (en) | 1998-04-17 |
IT8921786A0 (en) | 1989-09-21 |
IT1233753B (en) | 1992-04-14 |
KR910005841A (en) | 1991-04-27 |
ES2062240T3 (en) | 1994-12-16 |
CA2025855C (en) | 1997-12-23 |
JPH03145427A (en) | 1991-06-20 |
EP0418806A1 (en) | 1991-03-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0418806B1 (en) | Pharmaceutical compositions havin activity on the cutaneous microcirculation | |
US5104655A (en) | Polyunsaturated acids having vasokinetic action and pharmaceutical and cosmetic formulations containing them | |
US5436230A (en) | Use of a growth factor in a slimming composition | |
US5032400A (en) | Shark liver oil and garlic oil topical analgesic | |
US5679358A (en) | Formulations containing esculoside and the use thereof in the pharmaceutical and cosmetic fields | |
CH687127A5 (en) | A cosmetic preparation for hair loss as well as processes for their preparation. | |
KR960000855A (en) | L-carnitine salt and cosmetic composition and pharmaceutical composition for treating skin disease containing same | |
US6465514B1 (en) | Methods and compositions for the promotion of hair growth | |
US6132756A (en) | Use of sandalwood oil for the prevention and treatment of warts, skin blemishes and other viral-induced tumors | |
WO2006114188A1 (en) | Hair tonic | |
JPH02292215A (en) | External remedy and its usage | |
KR960010003A (en) | L-carnitine salt and cosmetic composition and pharmaceutical composition for treating skin disease containing same | |
US5945116A (en) | Compositions for the prevention and treatment of warts, skin blemishes and other viral-induced tumors | |
US4520132A (en) | Use of undecylenic acid to treat herpes labialis | |
JP2716739B2 (en) | Cosmetic composition having vasomotor action | |
KR100788608B1 (en) | Composition for improving hair growth | |
JPH0971513A (en) | Hair tonic | |
KR100573010B1 (en) | Composition comprising ketanserin and L-carnitine or an alkanoyl L-carnitine for the treatment of CRPS | |
USRE32990E (en) | Use of undercylenic acid to treat herpes labialis | |
KR0165938B1 (en) | Hair growth stimulating composition containing extract of artemisia apiaceahance | |
JP2002507198A (en) | Use of cis-6-hexadecenoic acid for the treatment of psoriasis, allergies and autoimmune disorders and for dry and sensitive skin | |
KR100444102B1 (en) | Cosmetic composition for trichogenousness containing Thujae semen extract | |
EP1150671A1 (en) | Use of pyrethroid compounds to promote hair growth | |
KR0165937B1 (en) | Hair growth stimulating composition containing extract of siegesbekiae herba | |
US20060280813A1 (en) | Pharmaceutical compositions containing bulbophyllum and their use for treating illnesses |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
17P | Request for examination filed |
Effective date: 19910905 |
|
17Q | First examination report despatched |
Effective date: 19920828 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Effective date: 19940105 Ref country code: AT Effective date: 19940105 Ref country code: SE Effective date: 19940105 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 19940105 Ref country code: DK Effective date: 19940105 |
|
REF | Corresponds to: |
Ref document number: 99542 Country of ref document: AT Date of ref document: 19940115 Kind code of ref document: T |
|
REF | Corresponds to: |
Ref document number: 69005753 Country of ref document: DE Date of ref document: 19940217 |
|
ITF | It: translation for a ep patent filed |
Owner name: ST. CONSUL.BREVETTUALE S.R.L. |
|
ET | Fr: translation filed | ||
NLV1 | Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act | ||
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19940930 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2062240 Country of ref document: ES Kind code of ref document: T3 |
|
26N | No opposition filed | ||
REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20060930 Year of fee payment: 17 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20070829 Year of fee payment: 18 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20070913 Year of fee payment: 18 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20070912 Year of fee payment: 18 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20071003 Year of fee payment: 18 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20071004 Year of fee payment: 18 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20070927 Year of fee payment: 18 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PCAR Free format text: PATENTANWALTSBUREAU STEUDTNER;AHORNWEG 12;5702 NIEDERLENZ (CH) |
|
BERE | Be: lapsed |
Owner name: *INDENA S.P.A. Effective date: 20080930 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20080918 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST Effective date: 20090529 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20080930 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20070918 Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20090401 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20080930 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20080930 Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20080930 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20080919 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20080918 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20080919 |